Rapidly dissolving dosage form

ABSTRACT

A particulate support matrix, and a dosage form made therefrom, and processes for making such support matrices and dosage forms, which disintegrate or dissolve in a matter of just a few seconds once placed into an aqueous environment. 
     First, a porous particulate powder matrix comprising at least two polymeric components which will serve as the dosage form matrix is produced. The polymeric components have different solubilities. In a second step, a pharmaceutical compound, for example an antihistamine, decongestant, or antibiotic is combined with the powder. Other additives may also be added to the mixture. In a third step the mixture is formed into a dosage form. Finally, in a fourth step, a coating may be formed upon the outer surface of the dosage form to enhance the intactness and durability of the dosage form.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part of U.S. Ser. No.08/487,268 , filed Jun. 7, 1995 , entitled RAPIDLY DISSOLVING DOSAGEFORM, now U.S. Pat. No. 5,776,491 , issued Jul. 7, 1998 , which is acontinuation-in-part of U.S. Ser. No. 08/191,237 , filed Feb. 3, 1994 ,entitled “RAPIDLY DISSOLVING ORAL DOSAGE FORM”, now U.S. Pat. No.5,807,576, which is a continuation-in-part of U.S. Ser. No. 08/187,670 ,filed Jan. 27, 1994 , now U.S. Pat. No. 5,595,761, issued on Jan. 21,1997.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not Applicable

BACKGROUND OF THE INVENTION

The present invention relates to a particulate support matrix, torapidly dissolving pharmaceutical dosage forms made therefrom, and toprocesses of preparing such a support matrix and such a dosage form.

The recent, current and projected growth of the elderly population inthe U.S. and abroad is well recognized. Currently, 12% of the U.S.population is 65 years of age or older and receives nearly 30% of themedications prescribed. It is anticipated that there may be a 10% to 60%increase in the demand for drugs by the elderly under some newgovernment programs. In spite of the disproportionately large demand forprescription pharmaceutical among the elderly, relatively littleattention has been directed to meeting the unique pharmacotherapeuticneeds of this age group. Drug products are currently designed for threegroups of individuals: infants, pediatrics and adults. The needs of theinfants are obviously different from those of children 2 to 12 years ofage and the needs of children are obviously different from those ofadults. However, the needs of the elderly population are beingoverlooked as they have special characteristics that necessitate dosageforms designed especially for them. Many older patients have difficultyswallowing tablets or capsules and yet the vast majority of dosage formsadministered to the elderly are tablets or capsules. Uncoated tabletsare convenient and economical to manufacture but are often difficult toswallow and often cause discomfort by “hanging” in the throat. Coatedtablets and capsules are somewhat easier to swallow but with increasingage and the large number of drug products that are administered to asingle individual, this is a source of apprehension. Liquid dosage formsare relatively easy to administer but are more costly, easily spilled,often do not taste good, occupy large volumes of space per dosage unit,and possess some inherent stability problems. As is evident, the needsof the elderly differ from those of other populations and deservespecial attention in new drug development, product formulation,posology, product packaging, product labeling, patient information, andproduct marketing and sales. A practical and new dosage form would be ofvalue for these patients.

Pediatric patients generally have difficulty swallowing until they reachthe age of about 10-16 years old. Younger pediatric patients generallytake either chewable tablets, crush and mix regular tablets withfood/juice, or take a liquid dosage form. Chewable tablets, generally agood dosage form, do not always taste good. Crushing and mixing regulartablets with food or juice, is time-consuming, messy and not alwayspractical. The difficulty of liquid dosage forms, i.e., syrups, is thatthey are bulky, do not always taste good, and that drugs are not asstable in a liquid dosage form as they are in a solid dosage form, suchas a tablet. A practical and new dosage form would also be of value forthese patients.

Incarcerated patients often will retain their medications within theoral cavity while pretending to swallow them. These can then beaccumulated and taken all at once for an enhanced drug effect.Obviously, this can be very dangerous. A dosage form which would notremain intact once placed in the oral cavity would be useful whentreating these patients.

There are currently several fast-dissolving products on the market.These products have a number of drawbacks including the manufacturingmethods used, taste masking, and pre- versus post-loading techniquesthat are required. One commercially available dosage form is prepared bya lyophilization, or freeze-drying, technique which is slow andexpensive. Because each “batch” of material must be handled in itsentirety, the tablet cannot be produced using a continuous process whereraw materials come in and finished product is output at the other end.This tablet can be either pre-loaded (i.e., the drug is added to thetablet matrix before the tablet is formed) or post loaded (the drug isadded after the tablet “blank” is prepared).

One difficulty with a freeze-dried dosage form is that of taste masking.To effectively mask the taste of poorly tasting drugs, it is generallynecessary to micro-encapsulate or nano-encapsulate them. Then, if theyare pre-loaded, the encapsulating shell material may dissolve during thetablet production process allowing the drug to leak into the tabletmatrix, resulting in a poorly tasting product. If the tablet ispost-loaded, the tablet may become disfigured causing the tablet to bedisposed of or handled again, adding extra expense to the process.

Another commercially available dosage form is prepared using solid statedissolution techniques. These manufacturing methods are expensive andadd additional cost to the tablet. This tablet must be post-loaded. Thisis necessary because drugs are generally soluble in the water andalcohol which is used in the preparation of the tablet. As with thefreeze-dried dosage form discussed above, when a solution of the drug ispost-loaded onto the matrix blank, often the tablets become disfigured.Another problem encountered with the solid state dissolution techniqueis the selection of a solvent material that will evaporate quickly butwill not attack the microcapsule shell surrounding the active drug.

Effervescent dosage forms contain substantial percentages of compoundsfor enhancing tablet breakup and dissolution which may also serve tomask the taste of certain medications. These tablets depend uponapproximate stoichiometric quantities of sodium bicarbonate and an acid,e.g., citric acid or tartaric acid, reacting to form CO₂ to break up thetablet in the mouth. The difficulty with the commercially availableeffervescent tablets is that the mouth tends to “foam” leaving anuncomfortable feeling to many.

BRIEF DESCRIPTION OF THE DRAWINGS

Not Applicable

SUMMARY OF THE INVENTION

According to one aspect of the invention, there is provided aparticulate matrix comprising a first polymeric component having apredetermined net charge when in solution, a second polymeric(solubilizing) component having a predetermined net charge when insolution of the same sign as the net charge of the first polymericcomponent, and a bulking agent, characterized in that the secondpolymeric component has a solubility in aqueous solution greater thanthat of the first polymeric component.

According to another aspect of the invention, there is provided arapidly dissolving pharmaceutical dosage for comprising: a particulatesupport matrix comprising a first polymeric component having apredetermined net charge when in solution, a second polymeric componenthaving a predetermined net charge when in solution of the same sign asthe net charge of the first polymeric component, and a bulking agent,and wherein the second polymeric component has a solubility in aqueoussolution greater than that of the first polymeric component; and apharmaceutical ingredient mixed with the particulate support matrix. Thesupport matrix is generally substantially completely disintegrablewithin less than about 20 seconds when the dosage form is introducedinto an aqueous environment so as to release the pharmaceuticalingredient to the aqueous environment.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention comprises a particulate support matrix, a dosageform made therefrom which disintegrates or dissolves in a matter of justa few seconds once placed into the oral cavity, or other aqueousenvironment and methods for making such support matrix and dosage form.This rapidly dissolving tablet or other dosage form made from the matrixdescribed herein has many of the characteristics of a regular tablet upto the point of administration, i.e., convenient size, stable, easy todispense, easily transportable, easy to alter the dose and easy toadminister. Upon placing this dosage form in the mouth, the saliva willserve to rapidly dissolve the dosage form and the patient in effect willswallow the medication in a liquid form. The rapid-dissolving tablets ofthe present invention will eliminate many of the problems inherent inthe other forms of orally-dissolving tablets described above since thematrix and active drug powders are blended and formed into tablets inthe same way as regular tablets, except that a very light compressionpressure is used in forming the tablets of the present invention.

Where used herein the term “dosage form” is meant to include any dosageform which is intended to be dissolved in any aqueous medium includingwater, saliva or other aqueous biological fluids or suspensions, and mayinclude tablets, capsules, caplets, boluses, powders cachets, pills andgranules.

If a drug entity has little or no taste, the dosage form will generallybe prepared to be almost tasteless. If a drug product does have acharacteristic, undesirable taste, the taste will preferably either bealtered by different mechanisms such as flavorings to make itacceptable, or the drug will be micro- or nano-encapsulated with acoating that dissolves at an acidic pH and incorporated into the tablet.This rapid dissolving tablet will not only provide the geriatric,pediatric and incarcerated populations with an easy to use tablet, butmay also result in long-term benefits such as enhanced patientcompliance, fewer hospital admissions due to poor compliance, andenhanced health and quality of life.

Furthermore, the application of this dosage form is not limited to oraldelivery as it is also applicable for use as a fast dissolving tabletwhen administered to other moist areas of orifices of the body, such asthe rectum.

Generally, the method of the present invention comprises up to foursteps. First, a porous particulate powder which will serve as the tabletsupport matrix is produced. In the second step, the pharmaceutical, forexample an antihistamine, decongestant, or antibiotic is combined withthe powder. Other additives may also be added to the mixture. In thethird step the mixture is formed into a tablet or other dosage form.Finally, in the fourth step, a coating may be applied to the outersurface of the tablet or other dosage form or the dosage form may beotherwise treated to enhance the intactness and durability of the tabletor other dosage form.

More particularly, the invention comprises a particulate support matrixfor use in forming a pharmaceutical dosage form and a process forproducing it. The process comprises the steps of providing an aqueouscomposition which further comprises (1) an aqueous medium, (2) a supportagent comprising a first polymeric component having a predetermined netcharge, a second polymeric component having a predetermined net chargeof the same sign as the first polymeric component, and a bulking agentand wherein the second polymeric component has a solubility in aqueoussolution greater than that of the first polymeric component, and (3) avolatilizing agent for enhancing the rate of vaporization of the aqueousmedium and for enhancing volume and porosity of the support agent duringdrying.

The particulate support matrix may optionally contain an acidifying oralkalizing agent for setting the predetermined net charge of thecomponents of the support agent. The first polymeric component andsecond polymeric component of the support matrix may be provided insolution or may be provided in solid form and dissolved within theaqueous medium to form the aqueous composition along with the bulkingagent. The aqueous composition is introduced as droplets into a dryingchamber heated to a temperature sufficient to evaporate substantiallyall of the aqueous medium and volatilizing agent from the droplets. Thisyields the support agent as a dried and expanded particulate formcomprising the particulate support matrix.

As contemplated herein, the support matrix, and the dosage form producedtherefrom, may comprise more than two polymeric support components. Insuch a case, the more than two polymeric support components are of thesame sign, and have a range of solubilities wherein one polymericsupport component is less soluble than the others and another componentis more soluble than the others. The most soluble polymeric component istherefore the primary polymeric solubilizing component of the presentinvention. It will be understood however that the other polymericcomponents may also contribute to the solubility of the support matrixin an aqueous environment.

The first polymeric component and the second polymeric component mayhave net charges which are closer to a neutral pH than is preferable foroptimal rapid dissolution. For example, when the first polymericcomponent is an acidic gelatin, and the second polymeric component is anacidic gelatin hydrolysate, the isoelectric points may be higher thanthe preferred pH, which is below 5.5. In such a case, it is desired toreduce the pH of the solution to a preferred pH by the addition of anacidifying agent, such as citric acid or acetic acid. This will shiftthe isoelectric points of the gelatin to pH levels within the preferredrange and will maintain them at such pH during the drying process.

However, when the first polymeric component and the second polymericcomponent have isoelectric pHs in their native form which are within thepreferred pH range of about 3.5 to 5.5 , it may be unnecessary to add anacidifying agent to the aqueous composition. For example, if the firstand second polymeric components are polypeptides comprising apreponderance of acidic amino acids, the polypeptides may haveisoelectric points which are sufficiently low. Similarly, if thepolypeptides comprise a preponderance of basic amino acids, thepolypeptides may have isoelectric points sufficiently basic to eliminatethe need for an alkalizing agent to raise the pH of the aqueouscomposition.

After the net charges of the first and second polymeric components arealtered (when necessary) either by an acidifying agent or by analkalizing agent, the altered net charges will be maintained by thepolymeric components due to their natural buffering capacity.

The completed particulate support matrix comprises (1) a first polymericcomponent having a net charge when in solution, (2) a second polymericcomponent having a net charge when in solution of the same sign as thenet charge of the first polymeric component, and (3) a bulking agent.The second polymeric component has a solubility in aqueous solutiongreater than that of the first polymeric component for enhancingdissolution of the particulate support matrix upon exposure to anaqueous environment. When the support matrix is introduced into anaqueous environment it is substantially completely disintegrable withinless than about 20 seconds. The support matrix may be substantiallycompletely disintegrable within less than about 10 seconds, or morepreferably within from about 1 second to about 6 seconds. Theparticulate support matrix preferably has a bulk density within a rangeof about 0.03 g/ml to about 0.15 g/ml. The particulate support matrixmay have a bulk density within a range of from 0.03 g/ml to about 0.3g/ml.

The first polymeric component may comprise a first polypeptide and thesecond polymeric component may comprise a second polypeptide. Morepreferably, the first polypeptide may be a non-hydrolyzed gelatin andthe second polypeptide may be a hydrolyze gelatin. Both the firstpolypeptide and the second polypeptide may have a net positive charge.Alternatively, the first polypeptide and the second polypeptide may havea net negative charge. The particulate support matrix may furthercomprise an agent for maintaining the net charge of the first polymericcomponent and the second polymeric component when it is desired tomaintain the net charges at pHs different from those of the pH of thenative first and second components in solution.

The invention further comprises a rapidly dissolving solidpharmaceutical dosage form, which is made from an active ingredient suchas a pharmaceutical product which is mixed and dispersed throughout theparticulate support matrix described herein and then formed into atablet. When this dosage form is introduced into an aqueous environmentthe support matrix is substantially completely disintegrable within lessthan about 20 seconds so as to release the pharmaceutical ingredient tothe aqueous environment. The support matrix may be substantiallycompletely disintegrable within less than about 10 seconds, or morepreferably in from about 1 second to about 6 seconds. The dosage formmay also contain a small amount of an effervescing agent (generally from0 to 5% of weight and preferably less than about 3%) for aiding in theinitial phase of disintegration of the dosage form, a binding agent, anda flavoring agent. Further, the dosage form may have a sintered orpolymeric coating on the external surface for enhancing the intactnessof the dosage form. The density of the dosage form is generally within arange of about 0.05 g/ml to about 0.4 g/ml, and is more preferablywithin the range of from 0.1 g/ml to about 0.2 g/ml.

PREPARATION OF THE PARTICULATE SUPPORT MATRIX

The particulate support matrix, in the preferred embodiment, is producedusing standard spray-drying techniques, well known to persons ofordinary skill in the art. The components of the composition which isused to produce the matrix include a support agent which comprises inone version a non-hydrolyzed gelatin and a hydrolyzed gelatin andadditionally a bulking agent for increasing the bulk and solubility ofthe support matrix and tablet formed therefrom. Another component is avolatilizing agent, having a volatility which exceeds that of water,such as an alcohol, preferably ethanol. Another optional component is anacidifying or alkalizing agent which functions to cause the componentsof the support agent to be maintained with a net charge, either positive(when the preferred pH of the composition is below neutral) or negative(when the preferred pH is above neutral). In a preferred version thesupport matrix is maintained with a net positive charge by an acidicagent such as citric acid. The composition further comprises an aqueousmedium such as water.

Critical physical factors in the spray drying process have to do withnet charge and solubility of the support agent (for example, ofproteins) and the evaporation characteristics of the volatilizing agent(for example, ethanol). In the preferred embodiment, the support agentis comprised of a first polymeric component and a second (solubilizing)polymeric component and a bulking agent. The second polymeric component(solubilizing component) contributes to the support function of thesupport matrix when in the dried particulate but also serves to enhancethe rate of dissolution of the support matrix once the tablet isintroduced into an aqueous environment such as the salivary environmentof the oral cavity. In one example of the preferred embodiment, thefirst and second components of the support agent comprise two differentforms of gelatin, an unmodified gelatin (the first polymeric component),and a hydrolyzed gelatin (the second polymeric component), and acttogether to form a support matrix in the dried particles. Both of theseforms of gelatin are commercially available. The hydrolyzed gelatinassists the unmodified gelatin as a structural component of the matrixbut it also functions to increase the solubility of the matrix. In anexperiment where the particulate matrix was formed only from theunmodified gelatin, water and alcohol, the powder dissolved inapproximately 25 seconds. When hydrolyzed gelatin was added to the sameformula, the powder produced therefrom dissolved in about 15 seconds.

In the preferred version of the invention, the solution of the proteinand protein hydrolysate is made acidic, preferably in the pH range ofabout 3.5 to 5.5 , and more preferably from about 4.0 to about 5.0. Thisacidity causes the protein components of the composition to have a netpositive charge at a pH which enhances repulsion of the proteincomponents. Together with or in lieu of gelatins, the first polymericsupport component and/or second polymeric component may be comprised ofother polymers which can maintain a net charge, including proteins,glycoproteins, acacia, alginic acid, pectin, tragacanth, and xanthan gumand which function in accordance with the present invention.

The following are examples of pairs of first polymeric support

and second polymeric (solubilizing) components (respectively) (1) acaciaand pectin, 2:1 ; and (2) tragacanth and xanthan gum, 1:3. The aboveratios are approximate.

In a preferred embodiment of the invention both the first polymericcomponent and the second polymeric component may comprise gelatin whichhas been hydrolyzed wherein the first component has a molecular weightgreater than that of the second component and wherein the secondcomponent has an aqueous solubility greater than that of the firstcomponent. Hydrolyzed gelatins have molecular weights ranging from 1,000to 12,000 daltons. Furthermore, the dosage form may comprise one or moreintermediate polymeric components having solubilities and molecularweights intermediate between the first polymeric component and secondpolymeric component contemplated herein.

The effect of the net positive charge of the protein (or polymer)molecules is to cause individual protein (or polymer) molecules to berepellent to each other when in solution thereby reducing the tendencyfor the protein (or polymer) molecules to “cling” to each other. As aresult, the protein (or polymer) molecules tend to remain repelled inthe solution and during the spray drying process while the droplets ofthe composition are drying into particles. As a result, the powderformed will be of relatively low bulk density, generally in the range offrom about 0.03 g/ml to about 0.3 g/ml. The bulking agent contributes tothe bulk and stability of the support matrix and further increases therate at which the support matrix will dissolve. Examples of bulkingagents are carbohydrates such as mannitol, sorbitol, sucrose, lactose,xylitol, and acacia. Mannitol and sorbitol are preferred bulking agents.

The incorporation of the ethanol (or another volatilizing agent) intothe solvent system functions to decrease the vaporization temperature ofthe solvent and contributes to the production of a more porous particlehaving a lesser bulk density and thus a greater bulk volume. It has beendiscovered that if water alone is used as the aqueous solvent, when thecomposition is introduced as droplets into the spray drying chamber, thedroplets will have a tendency to contract in size thus increasing indensity, as they traverse from the spray nozzle, through the dryingchamber, to the collecting chamber of the spray-drier unit. Byincorporating a volatilizing agent such as ethanol into the solvent,numerous pores and channels are formed within the structure of thedroplet as the solvent mixture volatilizes from the droplet during thedrying process. The particle formed from the droplet retains a higherporosity and low density and ever experiences expansion resulting in apowder having a larger bulk volume.

In one experiment, a control comprising a quantity of a formulaexcluding ethanol produced a dried particulate support matrix powderhaving a bulk density of 0.077 g/ml (specific bulk volume was about 13ml/g) and a bulk volume of 180 ml. The treatment comprised a comparableinitial quantity of the formula with ethanol added produced a driedparticulate support matrix powder having a bulk density of 0.049 g/ml(specific bulk volume was about 20.4 ml/g) and a bulk volume of 450 ml.The formula comprised, mannitol (10 g), sorbitol (5 g), citric acid (0.4g), sucrose (0.15 g), Explotab® (0.15 g), gelatin G8-275 (1 g), gelatinhydrolysate (1 g), and a quantity of water sufficient to produce avolume of 500 ml. The amount of ethanol added to the treatment was 150ml.

The term “bulk volume”, as used herein, is defined as the actual volumeof a quantity of particulate support matrix material. The term “truevolume” as used herein is defined as the volume of a quantity ofparticulate support matrix material after that quantity has beencompacted to eliminate the void space of the quantity. The term “bulkdensity” as used herein is defined as the mass of a quantity of theparticulate support material divided by the bulk volume of thatquantity. The term “specific bulk volume” is defined as the bulk volumeof a quantity of particulate support material divided by the mass ofthat quantity. The term “porosity” as used herein is a percentagedefined as:$\frac{{{bulk}\quad {volume}} - {{true}\quad {volume}}}{{bulk}\quad {volume}} \times 100.$

This result of a product having a greater bulk volume when ethanol isadded is apparently obtained by the lowering of the vaporizationtemperature of the solvent thus increasing the rate at which the solventis vaporized. The retention of the porous nature of the particle iscritical to the speed with which a tablet constructed of the materialdissolves. The porosity enhances the capillary movement of saliva intothe interior of the tablet thereby increasing the dissolution rate ofthe support matrix of the tablet.

The acidifying or alkalizing agent, when present in the compositionserves to maintain the net charge of the molecules of the supportmatrix. For example, in one preferred embodiment, the predetermined netpositive charge of the protein components is set by an acidifying agentsuch as citric acid. When the support matrix makes contact with anaqueous solution the proteins comprising the support matrix will have apositive charge and immediately repel each other as soon as theydissolve, thus causing the particles of the tablet to repel each other,enhancing the rapidness of disintegration of the tablet. A similarphenomenon may be effected by using an alkalizing agent such as sodiumbicarbonate as an alkalizing agent (causing the polymeric components ofthe support matrix to be negatively charged).

In the present invention, the first polymeric and second polymericcomponents of the support matrix together generally comprise from 2-35%of the dry components of the aqueous composition (percentage by weight,when the composition comprises the first polymeric and second polymericcomponents, the bulking agent and, optionally, the buffering agent) usedto form the particulate support matrix. More preferably, the range isfrom 5-25% and more preferably is from 10-20%. Most preferably the firstpolymeric and second polymeric components of the support matrix togethercomprise from 12-16% of dry portion of the aqueous composition.Generally, the first polymeric component and the second polymericcomponents are present in the formulation in a range of first polymericcomponent:second polymeric component ratios of from about 20:1 to about1:100 by weight, or in a range of from about 5:1 to about 1:40, or morepreferably in a range of from about 2:1 to about 1:25, or still morepreferably in a range of from about 1:2 to about 1:10.

In addition, the bulking agent of the support matrix generally comprisesfrom 45-97% of the dry components of the aqueous composition (percentageby weight) used to form the particulate support matrix. More preferably,the range is from 70-92% and more preferably is from 75-90%. Mostpreferably the bulking agent of the support matrix comprises from 80-85%of the dry portion of the aqueous composition. In addition, theacidifying or alkalizing agent of the support matrix generally comprisesfrom 0-30% of the dry components of the aqueous composition (percentageby weight) used to form the particulate support matrix. More preferably,the range is from 1-16% and more preferably is from 1-6%. Mostpreferably, when present, the acidifying or alkalizing agent of thesupport matrix comprises from 1-3% of the dry portion of the aqueouscomposition. As noted below, the matrix may further comprise a flavoringagent preferably added during the formation of the matrix. The flavoringagent may comprise from 0% to 10% of the aqueous composition in apreferred version and more preferably from 0.001% to 0.05%.

Formation of the Tablet

Before forming the particulate support matrix into a tablet, a quantityof the drug, medication, or pharmaceutical and any desired flavoringagent is added to a quantity of the particulate support matrix. Theoptional addition of a small amount of effervescent material serves toassist in the initial stage of the disintegration of the particles ofthe tablet. The tablet may be formed by methods known to those ofordinary skill in the art. For example, the tablet may be formed bydirect compression. Or, it may be formed by first adding a moisteningagent such as alcohol, then compressing or molding the composition. Or,it may be formed by first adding a binding agent such aspolyvinylpyrrolidone, then compressing or molding the composition into atablet. The dosage form described herein may include one or moreadjuvants which can be chosen from those known in the art includingflavors, diluents, colors, binders, fillers, compaction vehicles,effervescent agents, and non-effervescent disintegrants, such as thosedisclosed in U.S. Pat. No. 5,178,878, issued to Wheling et al. on Jan.12, 1993, and in U.S. Pat. No. 5,215,756, issued to Gole et al., on Jun.1, 1993, the specifications of which are hereby incorporated herein byreference. More specifically, the tablets may be composed of, but notlimited to, the following: gelatin (commercially available Pharmagel® Aand B, Type A, 275 Bloom, and Type B, 100 Bloom), hydrolyzed gelatin,sugars (mannitol, sucrose), organic acids (citric acid, succinic acid),sodium bicarbonate, ethyl alcohol, disintegrants such as Explotab®(sodium starch glycollate) and AcDiSol® (modified cellulose gum),starch, polyvinylpyrrolidone polymers, alginic acid, bulking andelectrical charge agents such as acacia, and polyethylene glycolpolymers.

Following the formation of the mixture into a tablet, it may be desiredto form a coating on or to apply a very thin coating to the externalsurface of the tablet. The function of the coating, when applied, is toenhance the intactness of the tablet. Due to the porous nature of thetablet, the tablet tends to be rather fragile and breakable andgenerally benefits from the added protection afforded by the coating.The coating may comprise a polymer, such a polyvinyl alcohol or apolyvinylpyrrolidone, which, when applied forms a polymeric “net” overand into the tablet. This “net” maintains the tablet intact but does notinhibit the capillary uptake by the tablet once placed in the aqueousenvironment of the oral cavity although dissolution time may be slightlyincreased when a coating is applied to the tablet (see Example 17).

Alternatively, a coating may be formed on the surface of the tablet ordosage form by a sintering process. Methods of sintering pharmaceuticaldosage forms are well known to those of ordinary skill in the art, andone is directed to pages 87-101 in the “Encyclopedia of PharmaceuticalTechnology, Vol. 14, 1996, (which is hereby incorporated herein byreference) for a review of this technology.

In a preferred version of the sintering technique used in the presentinvention, one or more PEGs preferably having MWs of 3000-6000, forexample, PEG 3350, are pulverized to a fine powder. A quantity of thisPEG powder (which may include one or more types of PEG) is mixed withthe drug/support matrix mixture defined elsewhere herein. A loose tabletor dosage form is formed and heated briefly, for example at 90° C. forabout 10 minutes. The PEG within the mixture melts, forming a thincoating on the tablet. No organic solvents are necessary in thissintering process. Examples of the sintering method are shown inExamples 36 and 37. One of ordinary skill in the art will be aware ofother methods of forming tablet coatings.

In preparation for forming the tablets, a tablet blend is produced bycombining a quantity of the particulate support matrix with a quantityof the pharmaceutical or drug and optionally with a quantity of aneffervescent blend, a binding solution and/or a flavoring (or theflavoring may be added during the formation of the matrix to produce aflavored matrix).

The pharmaceutical composition can be added at several different stagesof the formulation of the dosage form depending on the circumstances.The pharmaceutical can be added directly to the liquid compositionbefore or during the spray drying process at the inlet nozzle. Theresulting product can then be incorporated into the tablets.Alternatively, the pharmaceutical, in untreated or encapsulated form, ismixed with the particulate support matrix (after the spray dryingprocess, before or after adding the binder, if a binder is added) andthen formed into tablets. Alternatively, the pharmaceutical could beadded by direct application to the preformed tablet by spray coating ordrop coating.

As noted, the addition of the effervescent blend, the binding solution(also referred to herein as the binding agent) and the flavoring areoptional. In one embodiment, the binding solution and the effervescentblend may be added to the support matrix powder in a ratio of about20:10:1 (support matrix:binding solution: effervescent blend). Thebinding agent in one embodiment comprises from 0% to about 20% of thedry components of the aqueous composition and from 0% to 5% of theaqueous composition. The effervescent blend preferably consists of anapproximately stoichiometric ratio of citric/tartaric acids with sodiumbicarbonate in a powder form. In various versions, the effervescentblend may comprise the following ratios of components:

(1) citric acid:sodium bicarbonate, 1:1.2

(2) tartaric acid:sodium bicarbonate, 2:2.24

(3) citric acid:tartaric acid:sodium bicarbonate, 1:2:3.4

The blend is slightly acidic so there will be a slight tartness in themouth upon dissolution of the product. As is indicated above, the amountof effervescent blend present is minimal (from 0 to 5% of total weight)such that its fizzing properties are almost non-detectable in the mouth.Its presence enhances the separation of the porous particles andenhances capillarity during dissolution of the tablet within the oralcavity thereby decreasing dissolution time of the tablet (see Example15). The effervescent blend also enhances salivation in the oral cavity.

The binding solution in one version of the invention consists of 1%PVP-40 in ethanol (e.g., see Example 14). Other binding solutions mayconsist of mixtures of PEG 1000 and PEG 4000 in alcohol, or PEG 1000 andPVP 1000 in alcohol. Acetone may be substituted for ethanol or otheralcohols in these formulations. The binding solution may furthercomprise a quantity of a surface active agent such as sodium laurylsulfate for further increasing the dissolution rate of the dosage form.The binding solution, when used is generally incorporated by slowlymixing the solution with the spray dried powder, then drying at about40-50° C.

In one method used for forming the tablets, a quantity of the tabletblend is lightly compressed. The tablets thus produced may be coatedwith a very thin coating of an organic solution of a polymer, whichrapidly evaporates leaving a polymeric “net” on the surface of thetablet. This thin external “net” aids in keeping the tablets intactduring handling. Polymers may include, but are not limited to PVP andPVA. The coating may be applied by passing the tablet into a chamberhaving a saturated atmosphere of the coating material. Alternatively,the coating may be applied by lightly spraying the coating material ontothe surface of the tablet.

In another method for forming the tablets, a quantity of the tabletblend is moistened with ethanol then passed through a #40 mesh screenand immediately compressed into tablets and dried overnight at about 50°C. The tablets thus produced may be then coated with a very thin coatingof an organic solution of a polymer, which rapidly evaporates leaving a“net” on the surface of the tablet. Alternatively, as discussedelsewhere herein, the coating may be formed by sintering the tablet.

The present invention contemplates a tablet which is much lighter (forexample 50 mg) than a comparable typical commercially available tablet(for example 400-500 mg).

The present invention further contemplates a tablet which willdisintegrate within the oral cavity in less than about 20 seconds. Morepreferably, the tablet will disintegrate within less than about 10seconds. More preferably, the tablet will disintegrate within the oralcavity in less than about 6 seconds. Still more preferably, the tabletwill disintegrate in from about 1 second to about 4 seconds. The bulkdensity of the formed tablet is preferably in a range of from about 0.1g/ml to about 0.2 g/ml, but may be either less or greater than thebounds of this range, for example, 0.05 g/ml to 0.4 g/ml. Porosity maybe in a range of from about 50 to 75% in a preferred embodiment.

EXAMPLES

The following examples further illustrate compositions of the dosageform of the present invention including preferred versions and methodsof making the same; however these examples are not to be construed aslimitations of this invention.

Standardized Dissolution Testing Method

The testing method used to determine the dissolution of the tabletmaterial is a modification of the USP disintegration method whichinvolves the agitation of tablets in purified water at 37° C. Thepresent testing conditions used a 600 ml glass beaker with water atabout 37° C. The surface of the water was motionless. The water was notagitated. A fresh beaker of water was used for each test. To test thedissolution rate of the particulate matrix in powder form, the tip of a4″ stainless steel spatula was dipped into the powder and a quantity ofpowder equivalent to approximately 100 mg was removed from the containerand dropped onto the surface of the water from a distance ofapproximately 2.5 cm (1 inch). To test the dissolution rate of thesupport matrix in tablet form, a tablet was removed from its containerand placed on the tip of a 4″ stainless steel spatula. The tip of thespatula was held approximately 2.5 cm (1 inch) above the surface of thewater and the tablet allowed to slide off the spatula tip onto thewater. The testing method is an approximation of the in vitro use of thetablet. In actual practice, of course, the tablet will be placed on thetongue and a combination of the saliva dissolving the tablet and thetongue action aiding in its breakup will occur.

Where used herein, the term “substantially completely disintegrable”means that the dosage form is dissolved in solution such that it isvirtually entirely dispersed into the solution. This does notnecessarily imply total disintegration or dispersion. Disintegrationtime is the time from immersion for substantially complete dispersion ofthe tablet as determined by visual observation. As used herein, the term“substantially completely disintegrable” does not require dissolution ordisintegration of all microcapsules or other discrete inclusions of thedosage form, for some of these may be more slowly soluble than theparticulate matrix which comprises the critical dissolution enhancingcomponent of the dosage form.

Example 1

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 500 ml and a pH of 2.8:

Mannitol 30.0 g Gelatin G8-275 1.2 g Gelatin 1.2 g HydrolysateExplotab ® 0.6 g (Sodium Starch) Glycolate, NF) Acacia 0.6 g PVP-10 0.3g Citric Acid 1.5 g Tartaric Acid 1.5 g Ethanol 150 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 10, an aspirator setting of 5, a flow rate setting of4.27, an initial flow control setting of 700 (changing to 650 after thefirst time interval), and a vacuum setting of −20. Chamber temperatureswere measured at approximately 5 minute consecutive intervals during thedrying process. The temperatures at the flow inlet point were 156° C.,156° C.° , 159° C., 154° C. and 157° C. The temperatures at the flowoutlet point (the point where the dried product exits the drying chamberto product collector) were measured as 115° C., 111° C., 86° C., 109°C., and 108° C. The particulate support matrix product had a bulk volumeof about 140 ml, a specific bulk volume of 5.6 ml/g and a porosity of59.6%. The resulting matrix had a dissolution time of from 5 to 15seconds.

Example 2

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 500 ml and a pH of 6.4:

Sucrose 30.0 g Gelatin G8-275 0.9 g Gelatin 0.9 g Hydrolysate Explotab ®0.5 g Ethanol 150 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 10, an aspirator setting of 5 (which was changed to 7after the second time interval), a flow rate setting of 4.27, a flowcontrol setting of 700, and a vacuum setting of −20. Chambertemperatures were measured at approximately 5 minute consecutiveintervals during the drying process. The temperatures at the flow inletpoint were 154° C., 154° C., 133° C., 143° C., and 143° C. Thetemperatures at the flow outlet point (the point where the dried productexits the drying chamber to product collector) were measured as 104° C.,104° C., 90° C., 93° C., 93° C., and 93° C. The particulate supportmatrix product had a bulk volume of about 100 ml, a specific bulk volumeof 2.3 ml/g and a porosity of 8.8%. Dissolution time of the supportmatrix was 5-15 seconds.

Example 3

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 400 ml and a pH of 8.4:

Mannitol 60 g Gelatin G8-275 1.2 g Gelatin 1.2 g Hydrolysate Acacia 0.4g Explotab ® 0.4 g Alginic Acid 0.4 g PVP-40 0.6 g Sodium Bicarbonate2.4 g Ethanol 120 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 10, an aspirator setting of 5, a flow rate setting of4.27, an initial flow control setting of 700 (changing to 550 after thefirst time interval), and a vacuum setting of −20. Chamber temperatureswere measured at approximately 5 minute consecutive intervals during thedrying process. The temperatures at the flow inlet point were 154° C.,157° C., 157° C., 157° C., and 157° C. The temperatures at the flowoutlet point (the point where the dried product exits the drying chamberto product collector) were measured as 107° C., 108° C., 108° C., 108°C., and 108° C. The particulate support matrix product had a bulk volumeof about 60 ml, a specific bulk volume of 3.7 ml/g and a porosity of38.8%. Dissolution time of the matrix was about 5 seconds.

Example 4

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 400 ml and a pH of 3.0:

Mannitol 60 g Gelatin G8-275 1.2 g Gelatin 1.2 g Hydrolysate Acacia 0.8g Explotab ® 0.4 g PVP-40 0.6 g Citric Acid 0.9 g Tartaric Acid 0.9 gEthanol 120 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 10, an aspirator setting of 5, a flow rate setting of4.27, an initial flow control setting of 700 (changing to 600 after thefirst time interval and to 550 after the second time interval), and avacuum setting of −20. Chamber temperatures were measured atapproximately 5 minute consecutive intervals during the drying process.The temperatures at the flow inlet point were 155° C., 150° C. and 155°C. The temperatures at the flow outlet point (the point where the driedproduct exits the drying chamber to product collector) were measured as114° C., 109° C. and 108° C. The particulate support matrix product hada bulk volume of about 70 ml, a specific bulk volume of 5.11 ml/g and aporosity of 55.7%. Dissolution time of the support matrix was from 2-10seconds.

Example 5

The following components were added to a quantity of purified watersufficient to produce an acidic mixture “Part A” with a volume of 100ml:

Mannitol 20.0 g PVP-10,000 1.1 g Citric Acid 3.8 g Ethanol 20.0 ml

The following components were added to a quantity of purified water toproduce a basic mixture “Part B” with a volume of 100 ml:

Mannitol 20.0 g PVP-10,000 1.1 g Sodium Bicarbonate 5.0 g Ethanol 20.0ml

The two mixtures were mixed as introduced into a Buchi model 190 spraydrier with the heat settings shown below, aspirator settings shownbelow, a flow rate setting of 4.27, a flow control setting of 700, and avacuum setting of −20, as shown below. Chamber temperatures weremeasured at approximately 5 minute consecutive intervals during thedrying process. These temperatures are shown as inlet and outletreadings below. The particulate support matrix product had a bulk volumeof about 50 ml and a porosity of 31.2%.

Heating 10 11 12 10 12 12 15 14 Inlet, ° C. 49 72 90 87 104 102 107 108° F. 121  162  194  188  220 215 225 226 Outlet, ° C. 36 37 37 37 39 40  41  41  ° F. 96 98 98 98 102 104 106 106 Aspirator  6  6  6  6 15 15  20  20 

Example 6

The following components were added to a quantity of purified watersufficient to produce an acidic mixture “Part A” with a volume of 100ml:

Mannitol 22.5 g Gelatin 275 0.46 g Citric Acid 3.8 g Ethanol 30.0 ml

The following components were added to a quantity of purified water toproduce a basic mixture “Part B” with a volume of 200 ml:

Mannitol 22.5 g Gelatin 275 0.46 g Sodium Bicarbonate 5.0 g Ethanol 30.0ml

The mixture was introduced into a Buchi model 190 spray drier with heatsettings shown below, aspirator settings shown below, a flow ratesetting of 4.27, a flow control setting of 700, and a vacuum setting of−30. Chamber temperatures were measured at approximately 5 minuteconsecutive intervals during the drying process. The temperatures at theflow inlet point and outlet point are shown below. The particulatesupport matrix product had a bulk volume of about 70 ml and a porosityof 35.9% and a dissolution time of from 6-10 seconds.

Heating  5  6  9 10 11 12 Inlet, ° C. 33 34 38 66 66 79 Inlet, ° F. 9294 100  150  150  175  Outlet, ° C. 22 24 28 47 48 42 Outlet, ° F. 71 7683 117  118  108  Aspirator  5  6 10 12 10 12

Example 7

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 300 ml and a pH of 3.0:

Mannitol 30.0 g Gelatin G8-275 0.9 g Gelatin 0.9 g HydrolysateExplotab ® 0.6 g Tartaric Acid 1.8 g Ethanol 90.0 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 10, an aspirator setting of 5, a flow rate setting of4.27, an initial flow control setting of 700 (changing to 650 after thefirst time interval), and a vacuum setting of −20. Chamber temperatureswere measured at approximately 5 minute consecutive intervals during thedrying process. The temperatures at the flow inlet point were 156° C.,156° C., 156° C., 156° C., and 155° C. The temperatures at the flowoutlet point (the point where the dried product exits the drying chamberto product collector) were measured as 114° C., 108° C., 92° C., 89° C.,and 84° C. The particulate support matrix product had a bulk volume ofabout 150 ml, a specific bulk volume of about 6.3 ml/g and a porosity of64.0%. Dissolution time of the support matrix was about 5-15 seconds.

Example 8

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 500 ml and a pH of 8.7:

Mannitol 30 g Gelatin G8-275 1.2 g Gelatin 1.2 g Hydrolysate Acacia 0.6g Explotab ® 0.6 g PVP-40 0.3 g Sodium Bicarbonate 3.0 g Ethanol 150 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 10, an aspirator setting of 5, a flow rate setting of4.27, an initial flow control setting of 700 (changing to 650 after thefirst time interval), and a vacuum setting of −20. Chamber temperatureswere measured at approximately 5 minute consecutive intervals during thedrying process. The temperatures at the flow inlet point were 160° C.,157° C., 157° C., 156° C., and 155° C. The temperatures at the flowoutlet point (the point where the dried product exits the drying chamberto product collector) were measured as 115° C., 108° C., 107° C., 108°C., and 108° C. The particulate support matrix product had a relativelysmall bulk volume of 70 ml, a specific bulk volume of about 3.9 ml/g anda porosity of 41.5%. Dissolution time was about 5-20 seconds.

Example 9

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 500 ml and a pH of 3.5:

Mannitol 30 g Gelatin G8-275 0.9 g Gelatin 0.9 g Hydrolysate Explotab ®0.6 g Sucrose 1.5 g Citric Acid 0.45 g Ethanol 150 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 10, an aspirator setting of 7, a flow rate setting of4.27, an initial flow control setting of 700 (changing to 670 after thethird time interval), and a vacuum setting of −20. Chamber temperatureswere measured at approximately 5 minute consecutive intervals during thedrying process. The temperatures at the flow inlet point were 156° C.,155° C., 156° C., 155° C., and 155° C. The temperatures at the flowoutlet point (the point where the dried product exits the drying chamberto product collector) were measured as 117° C., 113° C., 106° C., 108°C., and 107° C. The particulate support matrix product had a bulk volumeof about 175 ml with a specific bulk volume of 6.6 ml/g and a porosityof 65.6%. Dissolution time was 3-4 seconds.

Example 10

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 1000 ml and a pH of4.5:

Mannitol 16.0 g Gelatin G8-275 2.0 g Gelatin 2.0 g HydrolysateExplotab ® 0.6 g PVP-40 0.16 g Sucrose 0.41 g Citric Acid 0.33 g Ethanol300 ml

The mixture was introduced into a Buchi model 190 spray dries with aheat setting of 9, an aspirator setting of 6 (changing to 7 after thefirst time interval), a flow rate setting of 5, an initial flow controlsetting of 700 (changing to 600 after the first time interval and to 500after the fourth time interval), and a vacuum setting of −20. Chambertemperatures were measured at approximately 5 minute consecutiveintervals during the drying process. The temperatures at the flow inletpoint were 139° C., 143° C., 144° C., 144° C., and 142° C. Thetemperatures at the flow outlet point (the point where the dried productexits the drying chamber to product collector) were measured as 102° C.,94° C., 97° C., 104° C., and 94° C. The particulate support matrixproduct had a bulk volume of about 150 ml, a specific bulk volume of 8.7ml/g and a porosity of 73.9%. Dissolution time was about 5-15 seconds.

Example 11

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 500 ml and a pH of 4.3:

Mannitol 15 g Gelatin G8-275 1.0 g Gelatin 1.0 g Hydrolysate Explotab ®0.6 g Ac Di Sol ® 0.3 g (Modified Cellulose Gum, NF) Sucrose 0.3 gCitric Acid 0.3 g Ethanol 150 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 9, an aspirator setting of 6, a flow rate setting of 5,a flow control setting of 620, and a vacuum setting of −20. Chambertemperatures were measured at approximately 5 minute consecutiveintervals during the drying process. The temperatures at the flow inletpoint were 148° C., 147° C., 147° C., 147° C., and 147° C. Thetemperatures at the flow outlet point (the point where the dried productexits the drying chamber to product collector) were measured as 116° C.,105° C., 103° C., 102° C., and 102° C. The particulate support matrixproduct had a bulk volume of about 100 ml, a specific bulk volume ofabout 7.5 ml/g and a porosity of 69.8%. Dissolution time was 5-10seconds.

Example 12

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 500 ml and pH of 4.10:

Sucrose 15.0 g Gelatin G8-275 1.0 g Gelatin 1.0 g Hydrolysate CitricAcid 0.3 g Explotab ® 0.58 g Ethanol 150 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 9, an aspirator setting of 6, a flow rate setting of 5,an initial flow control setting of 700 (changing to 650 after the secondtime interval), and a vacuum setting of −20. Chamber temperatures weremeasured at approximately 5 minute consecutive intervals during thedrying process. The temperatures at the flow inlet point were 154° C.,148° C., 145° C., 145C., 145° C. and 147° C. The temperatures at theflow outlet point (the point where the dried product exits the dryingchamber to product collector) were measured as 104° C., 104° C., 98° C.,95° C., 95° C. and 98° C. The very hygroscopic particulate supportmatrix product having a bulk volume of about 100 ml, a specific bulkvolume of about 4.05 ml/g and a porosity of 44.1% was obtained.Dissolution time was 5-15 seconds.

Example 13

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 500 ml and a pH of 4.0:

Sorbitol 15.0 g Mannitol 15.0 g Gelatin G8-275 1.0 g Gelatin 1.0 gHydrolysate Explotab ® 0.6 g Citric Acid 0.34 g Ethanol 150 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 8, an aspirator setting of 6, a flow rate setting of 5,an initial flow control setting of 700 (changing to 600 after the firsttime interval), and a vacuum setting of −20.

Chamber temperatures were measured at approximately 5 minute consecutiveintervals during the drying process. The temperatures at the flow inletpoint were 131° C., 131° C., 131° C., 131° C., 131° C. and 131° C. Thetemperatures at the flow outlet point (the point where the dried productexits the drying chamber to product collector) were measured as 94° C.,94° C., 94° C., 95° C. and 95° C. A granular particulate support matrixproduct having a bulk volume of about 250 ml, a specific bulk volume ofabout 6.8 ml/g and a porosity of 66.5% was obtained. Dissolution timewas about 2-3 seconds.

Example 14

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 1000 ml and a pH of4.5:

Mannitol 15.0 g Sorbitol 15.0 g Gelatin G8-275 2.0 g Gelatin 2.0 gHydrolysate Explotab ® 0.8 g Citric Acid 0.7 g PVP-40 0.3 g Sucrose 0.6g Ethanol 300 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 8, changing to 8.5 after the second time interval, anaspirator setting of 6, a flow rate setting of 5, a flow control settingof 700, and a vacuum setting of −20. Chamber temperatures were measuredat approximately 5 minute consecutive intervals during the dryingprocess. The temperatures at the flow inlet point were 139° C., 131° C.,141° C., 138° C., 137° C., 136° C. an 137° C. The temperatures at theflow outlet point (the point where the dried product exits the dryingchamber to product collector) were measured as 96° C., 89° C., 93° C.,92° C., 93° C., 93° C. and 93° C. The particulate support matrix producthad a bulk volume of about 300 ml, a specific bulk volume of about 12.7ml/g and a porosity of 82.1%. Dissolution time was 1-5 seconds. When abinding agent (PVP-40, 0.3 g) was added to a particulate matrix producedfrom this mixture, the dissolution time was 2-5 seconds in tablet form.

Example 15

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 1000 ml and a pH of4.0:

Mannitol 18.0 g Sorbitol 12.0 g Gelatin G8-275 2.0 g Gelatin 2.0 gHydrolysate Citric Acid 0.73 g Ethanol 300 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 8.8 which increased to 9.0 after the third timeinterval, an aspirator setting of 2 which changed to 3 after the secondtime interval, a flow rate setting of 5, a flow control setting of 700,and a vacuum setting of −20. Chamber temperatures were measured atapproximately 5 minute consecutive intervals during the drying process.The temperatures at the flow inlet point were 141° C., 137° C., 144° C.,144° C. and 145° C. The temperatures at the flow outlet point (the pointwhere the dried product exits the drying chamber to product collector)were measured as 107° C., 94° C., 96° C., 97° C., 99° C., and 92° C. Theparticulate support matrix product had a bulk volume of about 275 ml, aspecific bulk volume of about 21 ml/g and a porosity of 91.1%.Dissolution time was 1-5 seconds. A tablet produced from this matrixdissolved in about 3-5 seconds. When a quantity of an effervescent agentwas added to the matrix prior to forming the tablet, the dissolutiontime was reduced to 15 seconds.

Example 16

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 1000 ml and a pH of4.10:

Mannitol 21.0 g Sorbitol 9.0 g Gelatin G8-275 2.0 g Gelatin 2.0 gHydrolysate Citric Acid 0.75 g Sucrose 1.5 g Ethanol 300 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 8.9, an aspirator setting of 2 which changed to 1 afterthe third time interval, a flow rate setting of 5, a flow controlsetting of 600, and a vacuum setting of −20 which changed to −15 afterthe second time interval. Chamber temperatures were measured atapproximately 5 minute consecutive intervals during the drying process.The temperatures at the flow inlet point were 143° C., 144° C., 145° C.,145° C., 145° C. and 145° C. The temperatures at the flow outlet point(the point where the dried product exits the drying chamber to productcollector) were measured as 96° C., 95° C., 94° C., 94° C., 94° C. and94° C. The particulate support matrix product had a coarse texture and abulk volume of about 200 ml, a specific bulk volume of about 20.5 ml/gand a porosity of 89.1w. Dissolution time was 2-3 seconds.

Example 17

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 1000 ml and a pH of4.0:

Mannitol 21.0 g Sorbitol 9.0 g Gelatin G8-275 2.0 g Gelatin 2.0 gHydrolysate Citric Acid 0.76 g Explotab ® 0.6 g Ethanol 300 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 8.9, an aspirator setting of 2 which was changed to 1after the second time interval, a flow rate setting of 5, an initialflow control setting of 700 (changing to 650 after the second timeinterval), and a vacuum setting of −20. Chamber temperatures weremeasured at approximately 5 minute consecutive intervals during thedrying process. The temperatures at the flow inlet point were 141° C.,145° C., 143° C., 144° C., 144° C. and 144° C. The temperatures at theflow outlet point (the point where the dried product exits the dryingchamber to product collector) were measured as 92° C., 93° C., 91° C.,87° C., 87° C. and 870C. The particulate support matrix product had abulk volume of about 300 ml, a specific bulk volume of about 23 ml/g anda porosity of 89.8%. Dissolution time was about 2-3 seconds. A tabletformed from this mixture (except for Explotab®) had a dissolution timeof from 1-5 seconds. When the tablet was coated with 0.5% PVP-10 inchloroform, dissolution time was 2-5 seconds.

Example 18

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 1000 ml and a pH of4.2:

Mannitol 30.0 g Gelatin G8-275 2.0 g Gelatin 2.0 g Hydrolysate CitricAcid 0.46 g Sucrose 0.56 g Explotab ® 0.6 g Ethanol 300 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 8.9, an aspirator setting of 1, a flow rate setting of5, a flow control setting of 650, and a vacuum setting of −15. Chambertemperatures were measured at approximately 5 minute consecutiveintervals during the drying process. The temperatures at the flow inletpoint were 152° C., 142° C., 145° C., and 145° C. The temperatures atthe flow outlet point (the point where the dried product exits thedrying chamber to product collector) were measured as 90° C., 81° C.,86° C., and 87° C. A particulate support matrix product having a rathersmall bulk volume of about 150 ml, a specific bulk volume of about 15ml/g and a porosity of 85.5% was obtained. Dissolution time was about 5seconds.

Example 19

In a particularly preferred composition, the following components wereadded to a quantity of purified water sufficient to produce a mixturewith a volume of 1000 ml and a pH of 4.2:

Gelatin G8-275 1.0 g Gelatin 3.0 g Hydrolysate Mannitol 20.0 g Xylitol5.0 g Sorbitol 5.0 g Sucrose .68 g Citric Acid 1.0 g Propylene Glycol 10drops Acetic Acid, 6 drops Glacial Ethanol 300 ml

After spray drying this product produces approximately 300 mL. Toproduce a tablet, the above powder may be placed in the cavity of astandard tabletting machine and the pressure adjusted to yield a tabletwhich can remain intact for handling but retains its light weight.

Example 20

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 400 ml:

Mannitol 60.0 g Gelatin USP 2.0 g Gelatin 1.0 g Hydrolysate Acacia 1.0 gPVP-40 4.0 g Sodium Bicarbonate .15 g Acetone 120 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 9, an aspirator setting of 2, a flow rate setting of5.5, a flow control setting of 700, and a vacuum setting of −20. Chambertemperatures were measured at approximately 5 minute consecutiveintervals during the drying process. The temperatures at the flow inletpoint were 145° C., 156° C., 159° C. 154° C. and 157° C. Thetemperatures at the flow outlet point (the point where the dried productexits the drying chamber to product collector) were measured as 110° C.,100° C., 104° C., 103° C., and 103° C. The product had a specific bulkvolume of about 4.8 ml/g. The resulting matrix had a dissolution time ofless than 20 seconds. The mixture had a ratio of the first component(unmodified gelatin) and the second component (hydrolyzed gelatin) of2:1.

Example 21

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 400 ml:

Mannitol 60.0 g Gelatin USP 2.0 g Gelatin 1.0 g Hydrolysate PVP-40 6.0 gEthanol 120 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 10, an aspirator setting of 2 (which was increased to 5after the fourth time interval), a flow rate setting of 4.27, a flowcontrol setting of 700, and a vacuum setting of −20. Chambertemperatures were measured at approximately 5 minute consecutiveintervals during the drying process. The temperatures at the flow inletpoint were 156° C., 155° C., 155° C., 154° C., and 154° C. Thetemperatures at the flow outlet point (the point where the dried productexits the drying chamber to product collector) were measured as 118° C.,108° C., 108° C., 109° C., 110° C., and 110° C. The product had aspecific bulk volume of about 3.7 ml/g. Dissolution time of the supportmatrix was,less than 20 seconds. The mixture had a ratio of the firstcomponent (unmodified gelatin) and the second component (hydrolyzedgelatin) of 2:1.

Example 22

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 400 ml and a pH of 4.0:

Mannitol 60 g Gelatin USP 2.3 g Gelatin 1.3 g Hydrolysate PVP-40 4.3 gAcetone 120 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 9, an aspirator setting of 2, a flow rate setting of5.5, an initial flow control setting of 700, and a vacuum setting of−20. Chamber temperatures were measured at approximately 5 minuteconsecutive intervals during the drying process. The temperatures at theflow inlet point were 143° C., 143° C., 143° C., 143° C., and 143° C.The temperatures at the flow outlet point (the point where the driedproduct exits the drying chamber to product collector) were measured as100° C., 98° C., 90° C., 91° C., and 86° C. The particulate supportmatrix product had a specific bulk volume of 2.8 ml/g. Dissolution timeof the matrix was less than 5 seconds. The mixture had a ratio of thefirst component (unmodified gelatin) and the second component(hydrolyzed gelatin) of 1.8:1.

Example 23

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 400 ml:

Mannitol 60 g Gelatin USP 2.3 g Gelatin 1.3 g Hydrolysate PVP-40 4.3 gAcetone 120 ml

The mixture was introduced into a Buchi model 190 spray dries with aheat setting of 9, an aspirator setting of 113 changing to 105, a flowrate setting of 4.27 changing to 8.4, an initial flow control setting of700, and a vacuum setting of −40. Chamber temperatures were measured atapproximately 5 minute consecutive intervals during the drying process.The temperatures at the flow inlet point were 147° C. initially changingto 143° C. The temperatures at the flow outlet point (the point wherethe dried product exits the drying chamber to product collector) weremeasured at 113° C. changing to 105° C. The particulate support matrixproduct had a specific bulk volume of 2.8 ml/g. Dissolution time of thesupport matrix was less than 20 seconds. The mixture had a ratio of thefirst component (unmodified gelatin) and the second component(hydrolyzed gelatin) of 1.8:1.

Example 24

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 400 ml and a pH of 2.6:

Mannitol 60 g Gelatin A8-275 1.2 g Gelatin 1.0 g Hydrolysate Acacia 0.4g Explotab ® 0.6 g PVP-40 0.6 g Tartaric Acid 1.8 g Citric Acid 1.8 gAlgenic Acid 0.4 g Ethanol 120 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 10, an aspirator setting of 5, a flow rate setting of4.27, an initial flow control setting of 700 (changing to 500 after thefirst time interval), and a vacuum setting of −20. Chamber temperatureswere measured at approximately 5 minute consecutive intervals during thedrying process. The temperatures at the flow inlet point were 156° C.changing to 154° C. The temperatures at the flow outlet point (the pointwhere the dried product exits the drying chamber to product collector)were measured as 118° C. changing to 108° C. Dissolution time was lessthan 20 seconds. The mixture had a ratio of the first component(unmodified gelatin) and the second component (hydrolyzed gelatin) of1.2:1.

Example 25

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 1000 ml and a pH of3.6:

Mannitol 20 g Gelatin NF 2.0 g Gelatin 4.0 g Hydrolysate Sorbitol 5.0 gXylitol 5.0 g Propylene Glycol 10 drops 5% HAC q.s. Sucrose 0.66 gCitric Acid 1.0 g Ethanol 300 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 8.5, an aspirator setting of 0 changing to 20 1, a flowrate setting of 4.55, a flow control setting of 700, and a vacuumsetting of −20. Chamber temperatures were measured at approximately 5minute consecutive intervals during the drying process. The temperaturesat the flow inlet point were 136° C., 135° C., 135° C., 135° C., and137° C. The temperatures at the flow outlet point (the point where thedried product exits the drying chamber to product collector) weremeasured as 97° C., 95° C., 93° C., 90° C. and 85° C. Dissolution timewas less than 20 seconds. The mixture had a ratio of the first component(unmodified gelatin) and the second component (hydrolyzed gelatin) of1:2.

Example 26

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 1000 ml and a pH of3.6:

Mannitol 20.0 g Gelatin NF 1.5 g Gelatin 4.0 g Hydrolysate Sorbitol 10 gPropylene Glycol 10 drops HAC 15 drops Sucrose 0.65 g Citric Acid 1.5 gEthanol 300 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 8.4, an aspirator setting of 0 changing to 1, a flowrate setting of 4.55, a flow control setting of 700 (changing to 680after the first time interval), and a vacuum setting of −20. Chambertemperatures were measured at approximately 5 minute consecutiveintervals during the drying process. The temperature at the flow inletpoint was 135° C. The temperatures at the flow outlet point (the pointwhere the dried product exits the drying chamber to product collector)were measured as 88° C. changing to 83° C. The particulate supportmatrix product had a specific bulk volume of 18.7 ml/g. Dissolution timewas about 10 seconds. The mixture had a ratio of the first component(unmodified gelatin) and the second component (hydrolyzed gelatin) of1:2.7.

Example 27

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 1000 ml and a pH of3.5:

Mannitol 20 g Sorbitol 5.0 g Xylitol 5.0 g Gelatin NF 1.0 g Gelatin 3.0g Hydrolysate Acetic Acid, 15 drops Glacial Propylene Glycol 10 dropsSucrose 0.67 g Citric Acid 1.0 g Ethanol 300 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 8.2 an aspirator setting of 0, changing to 2, a flowrate setting of 3, a flow control setting of 680, and a vacuum settingof −20. Chamber temperatures were measured at approximately 5 minuteconsecutive intervals during the drying process. The temperature at theflow inlet point was 136° C. The temperatures at the flow outlet point(the point where the dried product exits the drying chamber to productcollector) were measured as 93° C., 90° C., 88° C., 84° C., and 81° C.The particulate support matrix product had a specific bulk volume ofabout 1.3 ml/g. Dissolution time was 1-15 seconds. The mixture had aratio of the first component (unmodified gelatin) and the secondcomponent (hydrolyzed gelatin) of 1:3.

Example 28

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 100 ml.

Sucrose 0.65 g Mannitol 18.0 g Sorbitol 5.0 g Xylitol 5.0 g Gelatin NF1.0 g Gelatin 3.0 g Hydrolysate Citric Acid 1.0 g Explotab ® 0.3 gPropylene Glycol 10 drops 5% HAC q.s. Ethanol 300 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 8.5, an aspirator setting of 0, changing to 2, a flowrate setting of 4.55, a flow control setting of 700, and a vacuumsetting of −20. Chamber temperatures were measured at approximately 5minute consecutive intervals during the drying process. The temperaturesat the flow inlet point were 139° C. changing to 137° C. Thetemperatures at the flow outlet point (the point where the dried productexits the drying chamber to product collector) were measured as 91° C.changing to 87° C. Dissolution time of the product was 5-15 seconds. Themixture had a ratio of the primary component (unmodified gelatin) andthe second component (hydrolyzed gelatin) of 1:3.

Example 29

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 1000 ml and a pH of3.9:

Sorbitol 11.0 g Mannitol 19.0 g Gelatin NF 1.0 g Gelatin 4.0 gHydrolysate Sucrose 0.66 g Propylene Glycol 10 drops 5% HAC q.s. CitricAcid 1.0 g Ethanol 300 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 8.5, an aspirator setting of 0 changing to 0.5, a flowrate setting of 4, a flow control setting of 600, and a vacuum settingof −20.

Chamber temperatures were measured at approximately 5 minute consecutiveintervals during the drying process. The temperatures at the flow inletpoint were 138° C. changing to 133° C. The temperatures at the flowoutlet point (the point where the dried product exits the drying chamberto product collector) were measured as 102° C. changing to 89° C.Dissolution time was less than 20 seconds. The mixture had a ratio ofthe primary component (unmodified gelatin) and the second component(hydrolyzed gelatin) of 1:4.

Example 30

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 1000 ml and a pH of3.5.

Mannitol 18.0 g Sorbitol 5.0 g Xylitol 5.0 g Gelatin NF .75 g Gelatin3.5 g Hydrolysate Explotab ® 0.3 g Citric Acid 1.0 g Propylene Glycol 10drops Sucrose 0.65 g Ethanol 300 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 8.5, an aspirator setting of 0, changing to 4, a flowrate setting of 4.55, a flow control setting of 700, and a vacuumsetting of −20. Chamber temperatures were measured at approximately 5minute consecutive intervals during the drying process. The temperaturesat the flow inlet point were 147° C. changing to 136° C. Thetemperatures at the flow outlet point (the point where the dried productexits the drying chamber to product collector) were measured as 98° C.changing to 89° C. Dissolution time was less than 20 seconds. Themixture had a ratio of the primary component (unmodified gelatin) andthe second component (hydrolyzed gelatin) of 1:4.67.

Example 31

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 1000 ml and a pH of3.6:

Mannitol 18.0 g Sorbitol 5.0 g Xylitol 5.0 g Sucrose 0.65 g Gelatin NF0.5 g Gelatin 3.5 g Hydrolysate Citric Acid 1.0 g 5% HAC 10 dropsPropylene Glycol 10 drops Explotab ® 0.3 g Ethanol 300 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 8.5, an aspirator setting of 0 which changed to 1, aflow rate setting of 4.55, a flow control setting of 700, and a vacuumsetting of −20. Chamber temperatures were measured at approximately 5minute consecutive intervals during the drying process. The temperaturesat the flow inlet point were 139° C. changing to 135° C. Thetemperatures at the flow outlet point (the point where the dried productexits the drying chamber to product collector) were measured as 98° C.changing to 88° C. The particulate support matrix product had adissolution time of less than 20 seconds. The mixture had a ratio of theprimary component (unmodified gelatin) and the second component(hydrolyzed gelatin) of 1:7.

Example 32

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 1000 ml and a pH of3.5:

Mannitol 16.0 g Sorbitol 7.0 g Gelatin NF 0.5 g Gelatin 5.0 gHydrolysate Citric Acid 1.0 g Sucrose 0.65 g Xylitol 5.0 g Explotab ®0.3 g 5% HAC q.s. Polyethylene Glycol 10 drops Ethanol 300 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 8.5, an aspirator setting of 0 which changed to 1, aflow rate setting of 4.55, a flow control setting of 700 and a vacuumsetting of −20. Chamber temperatures were measured at approximately 5minute consecutive intervals during the drying process. The temperaturesat the flow inlet point were 141° C. changing to 132° C. Thetemperatures at the flow outlet point (the point where the dried productexits the drying chamber to product collector) were measured as 92° C.changing to 88° C. to 91° C. The particulate support matrix product hada dissolution time of less than 20 seconds. The mixture had a ratio ofthe primary component (unmodified gelatin) and the second component(hydrolyzed gelatin) of 1:10.

Example 33

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 1000 ml and a pH of3.5:

Mannitol 16.0 g Sorbitol 7.0 g Xylitol 5.0 g Sucrose 0.65 g Gelatin NF0.5 g Gelatin 7.0 g Hydrolysate Citric Acid 1.0 g Explotab ® 0.3 g 5%HAC q.s. Polyethylene Glycol 10 drops Ethanol 300 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 8.5, an aspirator setting of 0 changing to 1, a flowrate setting of 4.55, an initial flow control setting of 700, and avacuum setting of −20. Chamber temperatures were measured atapproximately 5 minute consecutive intervals during the drying process.The temperature at the flow inlet point was 136° C. to 138° C. Thetemperatures at the flow outlet point (the point where the dried productexits the drying chamber to product collector) were measured as 99° C.to 90° C. The particulate support matrix product had a dissolution timeof less than 20 seconds. The mixture had a ratio of the primarycomponent (unmodified gelatin) and the second component (hydrolyzedgelatin) of 1:14.

Example 34

The following components were added to a quantity of purified watersufficient to produce a mixture with a volume of 500 ml:

Mannitol 10.0 g Sorbitol 2.5 g Xylitol 2.5 g Sucrose 0.325 g Gelatin0.75 g Gelatin 2.0 g Hydrolysate Acetic Acid 8 drops Tartaric Acid 0.75g Propylene Glycol 5 drops Flavoring (see below) Ethanol 150 ml Purifiedwater to . . . 500 ml

The mixture was introduced into a Buchi model 190 spray drier with aheat setting of 8, an aspirator setting of 0.5, a flow rate setting of4.5, an initial flow control setting of 600, and a vacuum setting of−20. The temperature at the flow inlet point was 133° C. Thetemperatures at the flow outlet point (the point where the dried productexits the drying chamber to product collector) was measured as 89° C.The particulate support matrix product had a dissolution time of lessthan 20 seconds. The mixture had a ratio of the primary component(unmodified gelatin) and the second component (hydrolyzed gelatin) of1:2.67.

Separate formulations were made with each of the flavorings andquantities thereof listed below. Each formulation produced a flavoredsupport matrix having the corresponding density. Densities werecalculated based on the volume associated with 18.825 gm of supportmatrix.

Flavoring Quantity Used Powder Volume Density Anise oil, NF 0.5 mL 160mL 0.118 Banana extract 10 mL 140 mL 0.134 (Food grade) Grape,Artificial 1 mL 180 mL 0.105 3 mL 170 mL 0.111 Lemon Oil, NF 0.25 mL 140mL 0.134 Menthol, USP 1 g 100 mL 0.188 Methyl salicylate, 1 mL 170 mL0.111 Reagent 3 mL 160 mL 0.118 Orange oil, USP 0.2 mL 50 mL 0.376 1 mL45 mL 0.418 Orange extract 3 mL 150 mL 0.126 (Food grade) Peppermintoil, 0.5 mL 60 mL 0.314 Laboratory grade Strawberry 3 mL 160 mL 0.118(Imitation Extract)

Example 35

The following are examples of coating compositions referred to abovewhich can be used to coat the formed tablets. Coating agents can beapplied by dropping, by spraying or by passing the tablet through anenvironment saturated with the coating agent.

I. PVP-40 10% PEG 1450 10% Chloroform 80% II. PVP-10 100 mg AbsoluteAlcohol 5 ml Ether 18 ml III. PEG 1450 170 mg Absolute Alcohol 7 mlEther 14 ml IV. PVP-10 0.5% PVP-40 0.5% PEG 1540 1.0% Chloroform 98% V.PVP-10 1.0% PVP-40 1.0% PEG 1450 1% PEG 3350 1% Chloroform 96% VI. PEG1450 5% PEG 3350 5% Chloroform 90% VII. PEG 1450 5% PEG 3350 5% PVP10/PVP40 0.1-0.5% (one or the other) Chloroform 89.5% VIII. PEG 3350 20.g Acetone to make 100 ml

Acetone may be substituted for chloroform or ether in the aboveformulations. Formulas VI and VIII are preferred coating compositionsdue to their tendency to leave tablet volume unaffected. Solvents otherthan ether, alcohol and chloroform may be used. These include ethylacetate and other types of organic solvents.

As noted above, forming a coating on the tablet by a sintering method isalso a preferred coating method. Examples 36-37 describe processes formaking tablets wherein a sintering method is used to form a coating onthe tablet.

Example 36

A. Product A

1. Preparation of sintered placebo tablets:

a) Combine 170 mg of the support matrix (60 mesh sieve) with 170 mg of afine powder mixture of 50% PEG-3350, 7.5% PEG-4000 and 32.5% PEG-6000.

b) Blend thoroughly and then compress into tablets. Heat tablets at 90°C. for ten minutes in the oven. Remove.

B. Product B

1. Preparation of Sintered tablets of chlorpheniramine maleate

a) Combine chlorpheniramine maleate 4 mg, L-lysine monohydrochloride 7.5mg, Urea powder (325 mesh) 0.5 mg, DL-glutamic acid 0.25 mg, SaccharinSodium 0.75 mg, and 166 mg of the support matrix with 160 mg of a finepowder mixture of 50% PEG-3350, 17.5% PEG-4000 and 32.5% PEG-6000.

b) Blend completely, and then compress into tablets. Heat at 90° C. forten minutes in the oven.

Example 37

1. Preparation of sintered tablets of chlorpheniramine maleate(alternative version):

a) Chlorpheniramine maleate 4 mg, L-lysine monohydrochloride 7.5 mg,Urea (fine powder) 0.5 mg, DL-glutamic acid 0.25 mg, Saccharin Sodium0.75 mg, support matrix powder 166 mg and PEG-4000 powder (325 mesh) 166mg were combined.

b) The uniformly mixed powders were moistened with 15 drops of 10%propylene glycol in isopropyl alcohol to ensure that active drug wasuniformly adsorbed onto the network structure of support matrix to meetuniformity of dosage units. The slightly moistened mixture of powderswas placed in the oven at 40° C. for 15 minutes to remove organicsolvent and was finally compressed into tablets.

c) The tablets thus obtained were placed in the oven at 90° C. for 10minutes and then stored in a desiccator and packaged.

Changes may be made in the construction and the operation of the variouscomponents, elements and assemblies described herein or in the steps orthe sequence of steps of the methods described herein without departingfrom the spirit and scope of the invention as defined in the followingclaims.

What is claimed is:
 1. A rapidly dissolving pharmaceutical dosage form,comprising: a particulate support matrix comprising a first polypeptidecomponent having a predetermined net charge, a second polypeptidecomponent having a predetermined net charge of the same sign as the netcharge of the first polypeptide component, and a bulking agent, andwherein the first polypeptide component and the second polypeptidecomponent together comprise about 2% to 35% by weight of the particulatesupport matrix and wherein the bulking agent comprises about 45% to 97%by weight of the particulate support matrix, and wherein the secondpolypeptide component has a solubility in aqueous solution greater thanthat of the first polypeptide component; and a pharmaceuticalingredient; and wherein when the dosage form is introduced into anaqueous environment the support matrix is substantially completelydisintegrable within less than about 20 seconds.
 2. The dosage form ofclaim 1 further comprising up to 5% of an effervescing agent.
 3. Thedosage form of claim 1 further comprising a binding agent.
 4. The dosageform of claim 1 further comprising a flavoring agent.
 5. The dosage formof claim 1 further comprising a surface coating.
 6. The dosage form ofclaim 1 further comprising a sintered surface.
 7. The dosage form ofclaim 1 wherein when the dosage form is introduced into an aqueousenvironment the support matrix is substantially completely disintegrablewithin less than about 10 seconds.
 8. The dosage form of claim 1 whereinwhen the dosage form is introduced into an aqueous environment thesupport matrix is substantially completely disintegrable in from about 1second to about 6 seconds.
 9. The dosage form of claim 1 wherein thefirst polypeptide component and the second polypeptide component bothhave a net positive charge.
 10. The dosage form of claim 1 wherein thefirst polypeptide component and the second polypeptide component bothhave a net negative charge.
 11. The dosage form of claim 1 wherein thefirst polypeptide component and the second polypeptide component eachcomprise a gelatin which has been hydrolyzed.
 12. A rapidly dissolvingpharmaceutical dosage form, comprising: a particulate support matrixcomprising a non-hydrolyzed gelatin component having a predetermined netcharge, a hydrolyzed gelatin component having a predetermined net chargeof the same sign as the net charge of the non-hydrolyzed gelatincomponent, and a bulking agent and wherein the non-hydrolyzed gelatincomponent and the hydrolyzed gelatin component together comprise fromabout 2% to 35% of the particulate support matrix and the bulking agentcomprises from about 45% to 97% of the particulate support matrix, andwherein the hydrolyzed gelatin component has a solubility in aqueoussolution greater than that of the non-hydrolyzed gelatin component; anda pharmaceutical ingredient; and wherein when the dosage form isintroduced into an aqueous environment the support matrix issubstantially completely disintegrable within less than about 20seconds.
 13. The dosage form of claim 12 wherein the non-hydrolyzedgelatin component and the hydrolyzed component both have a net positivecharge.
 14. The dosage form of claim 12 wherein the non-hydrolyzedgelatin component and the hydrolyzed gelatin component both have a netnegative charge.
 15. The dosage form of claim 12 further comprising upto 5% of an effervescing agent.
 16. The dosage form of claim 12 furthercomprising a binding agent.
 17. The dosage form of claim 12 furthercomprising a flavoring agent.
 18. The dosage form of claim 12 furthercomprising a surface coating.
 19. The dosage form of claim 12 furthercomprising a sintered surface.
 20. The dosage form of claim 12 whereinwhen the dosage form is introduced into an aqueous environment thesupport matrix is substantially completely disintegrable within lessthan about 10 seconds.
 21. The dosage form of claim 12 wherein when thedosage form is introduced into an aqueous environment the support matrixis substantially completely disintegrable within less than about 10seconds.
 22. A rapidly dissolving pharmaceutical dosage form,comprising: a particulate support matrix comprising a first gelatincomponent having a predetermined net charge, a second gelatin componenthaving a predetermined net charge of the same sign as the net charge ofthe first gelatin component, and a bulking agent and wherein the firstgelatin component and the second gelatin component together comprisefrom about 2% to 35% of the Particulate support matrix and the bulkingagent comprises from about 45% to 97% of the particulate support matrix,and wherein the second gelatin component has a solubility in aqueoussolution greater than that of the first gelatin component; and apharmaceutical ingredient; and wherein when the dosage form isintroduced into an aqueous environment the support matrix issubstantially completely disintegrable within less than about 20seconds.
 23. The dosage form of claim 22 wherein the first gelatincomponent comprises a first hydrolyzed gelatin and the second gelatincomponent comprises a second hydrolyzed gelatin.
 24. The dosage form ofclaim 22 further comprising up to 5% of an effervescing agent.
 25. Thedosage form of claim 22 further comprising a binding agent.
 26. Thedosage form of claim 22 further comprising a flavoring agent.
 27. Thedosage form of claim 22 further comprising a surface coating.
 28. Thedosage form of claim 22 further comprising a sintered surface layer. 29.The dosage form of claim 22 wherein when the dosage form is introducedinto an aqueous environment the support matrix is substantiallycompletely disintegrable within less than about 10 seconds.
 30. Thedosage form of claim 22 wherein when the dosage form is introduced intoan aqueous environment the support matrix is substantially completelydisintegrable in from about 1 second to about 6 seconds.
 31. The dosageform of claim 22 wherein the first gelatin component and the secondgelatin component both have a net positive charge.
 32. The dosage formof claim 22 wherein the first gelatin component and the second gelatincomponent both have a net negative charge.
 33. The dosage form of claim1 wherein the second polypeptide component has a molecular weight whichis less than the molecular weight of the first polypeptide component.34. The dosage form of claim 22 wherein the second gelatin component hasa molecular weight which is less than the molecular weight of the firstgelatin component.